The invention pertains to the discovery and use of new compounds that inhibit the enzymatic activity of picornaviral 3C proteases, specifically rhinovirus proteases (RVPs), as well as retard viral growth in cell culture.
The picornaviruses are a family of tiny non-enveloped positive stranded RNA containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, menigovirus, foot and mouth viruses, hepatitis A virus and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies to cure the common cold, only treatments that relieve the symptoms.
One strategy that may be useful to treat picornaviral infections is by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. In theory, inhibition of 3C proteases can block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective, small molecules that are specifically recognized, may represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
The present invention is directed to compounds that functions as picornaviral 3C protease inhibitors, particularly those that have antiviral activity. It is further directed to the preparation and use of such 3C protease inhibitors. The Inventors demonstrate that the compounds of the present invention bind to rhinovirus 3C proteases and preferably have antiviral cell culture activity. The enzymatic inhibition assays used reveal that these compounds can bind irreversibly, and the cell culture assays demonstrate that these compounds can possess antiviral activity.
The present invention is directed to compounds of the formula (I): 
wherein
R1 is H, F, an alkyl group, OH, SH, an O-alkyl group, or an S-alkyl group;
R2 and R5 are independently selected from H, 
xe2x80x83or an alkyl group, wherein said alkyl group is different from 
xe2x80x83with the proviso that at least one of R2 or R5 must be 
xe2x80x83and wherein, when R2 or R5 is 
X is xe2x95x90CH or xe2x95x90CF and Y1 is xe2x95x90CH or xe2x95x90CF
or X and Y1 together with Qxe2x80x2 form a three-membered ring
in which Qxe2x80x2 is xe2x80x94C(R10)(R11)xe2x80x94 or xe2x80x94Oxe2x80x94, X is xe2x80x94CHxe2x80x94 or xe2x80x94CFxe2x80x94, and Y1 is xe2x80x94CHxe2x80x94, xe2x80x94CFxe2x80x94, or xe2x80x94C(alkyl)xe2x80x94, where R10 and R11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
or X is xe2x80x94CH2xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94CHFxe2x80x94, or xe2x80x94Sxe2x80x94, and
Y1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR12xe2x80x94, xe2x80x94C(R13)(R14)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, or xe2x80x94C(CR13R14)xe2x80x94
wherein R12 is H or alkyl, and R13 and R14 independently are H, F, or an alkyl group, or, together with the atoms to which they are bonded, form a cycloalkyl group or a heterocycloalkyl group;
and A1 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), Pxe2x80x94OR15, or Pxe2x80x94NR15R16 
wherein R15 and R16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are bonded, form a heterocycloalkyl group;
and D1 is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
and B1 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18 
wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, or, wherein any two of R17, R18, and R19, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
and with the provisos that when D1 is the moiety xe2x89xa1N with a lone pair of electrons capable of forming a hydrogen bond, B1 does not exist; and when A1 is an sp3 carbon, B1 is not xe2x80x94NR17R18 when D1 is the moiety xe2x80x94NR25R26 with a lone pair of electrons capable of forming a hydrogen bond, wherein R25 and R26 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
and wherein D1xe2x80x94A1xe2x80x94B1 optionally forms a nitro group where A1 is N;
and wherein, when R2 or R5 is 
X is xe2x95x90CH or xe2x95x90CF and Y2 is xe2x95x90C, xe2x95x90CH or xe2x95x90CF,
or X and Y2 together with Qxe2x80x2 form a three-membered ring
in which Qxe2x80x2 is xe2x80x94C(R10)(R11)xe2x80x94 or xe2x80x94Oxe2x80x94, X is xe2x80x94CHxe2x80x94 or xe2x80x94CFxe2x80x94, and Y2 is xe2x80x94CHxe2x80x94, xe2x80x94CFxe2x80x94, or xe2x80x94C(alkyl)xe2x80x94, where R10 and R11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
or X is xe2x80x94CH2xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94CHFxe2x80x94, or xe2x80x94Sxe2x80x94, and
Y2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Rxe2x80x212)xe2x80x94, xe2x80x94C(Rxe2x80x213)(Rxe2x80x214)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, or xe2x80x94C(CRxe2x80x213Rxe2x80x214)xe2x80x94
wherein Rxe2x80x212 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94ORxe2x80x213, xe2x80x94NRxe2x80x213Rxe2x80x214, xe2x80x94C(O)xe2x80x94Rxe2x80x213, xe2x80x94SO2Rxe2x80x213, or xe2x80x94C(S)Rxe2x80x213, and Rxe2x80x213 and Rxe2x80x214, independently are H, F, or an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
and wherein any combination of Y2, A2, B2, and D2 forms a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
and A2 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), Pxe2x80x94OR15, or Pxe2x80x94NR15R16 
wherein R15 and R16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are bonded, form a heterocycloalkyl group;
and D2 is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
and B2 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NR17R18, xe2x80x94NR19NR17R18, or xe2x80x94NR17OR18 
wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, or, wherein any two of R17, R18, and R19, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
R3 and R6 are independently H, F, or an alkyl group;
R4 is H, OH, or a suitable organic moiety;
Z and Z1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94C(O)R21, xe2x80x94CO2R21, xe2x80x94CN, xe2x80x94C(O)NR21R22, xe2x80x94C(O)NR21OR22, xe2x80x94C(S)R21, xe2x80x94C(S)NR21R22, xe2x80x94NO2, xe2x80x94SOR21, xe2x80x94SO2R21, xe2x80x94SO2NR21R22, xe2x80x94SO(NR21)(OR22), xe2x80x94SONR21, xe2x80x94SO3R21, xe2x80x94PO(OR21)2, xe2x80x94PO(R21)(R22), xe2x80x94PO(NR21R22)(OR23), xe2x80x94PO(NR21R22)(NR23R24), xe2x80x94C(O)NR21NR22R23, or xe2x80x94C(S)NR21NR22R23,
wherein R21, R22, R23, and R24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
or Z1, as defined above, together with R1, as defined above, and the atoms to which Z and R1 are bonded, form a cycloalkyl or heterocycloalkyl group,
or Z and Z1, both as defined above, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group;
and pharmaceutically acceptable prodrugs, salts, and solvates thereof;
and wherein these compounds, pharmaceutically acceptable prodrugs, salts, and solvates preferably have antipicornaviral activity with an EC50 less than or equal to 100 xcexcM in the HI-HeLa cell culture assay, and more preferably antirhinoviral activity with an EC50 less than or equal to 100 xcexcM in the HI-HeLa cell culture assay and/or anticoxsachieviral activity with an EC50 less than or equal to 100 xcexcM in the HI-HeLa cell culture assay.
The present invention is also directed to several methods of preparing compounds of formula (I), defined above. One method according to the invention involves converting a compound of formula Q 
wherein R1, R2 and R5 are as defined above, and P1 is a protective group, preferably benzyloxy carbonyl or t-butoxycarbonyl, or a salt or solvate thereof, to a compound of formula I, as defined above, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
Another method according to the invention involves converting a compound of the formula B: 
wherein R1, R2 and R5 are as defined above, or a salt or solvate thereof, to a compound of formula I, as defined above, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
Another method according to the invention involves converting a compound of formula O: 
wherein R1, R2, R5, Z and Z1 are as defined above and P1 is a protective group, preferably benzyloxy carbonyl or t-butoxycarbonyl, or a salt or solvate thereof, to a compound of formula I, as defined above, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
Another method according to the present invention involves converting a compound of formula P: 
wherein R1, R2, R5, Z and Z1 are as defined above, or a salt or solvate thereof, to a compound of formula I, as defined above, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
The present invention relates to compounds of the formula I 
wherein R1, R2, R3, R4, R5, R6, Z and Z1 are as defined above, and to the pharmaceutically acceptable prodrugs, salts, and solvates thereof, where these compounds, pharmaceutically acceptable prodrugs, salts, and solvates preferably have antipicornaviral activity with an EC50 less than or equal to 100 xcexcM in the HI-HeLa cell culture assay, and more preferably antirhinoviral activity with an EC50 less than or equal to 100 xcexcM in the HI-HeLa cell culture assay and/or anticoxsachieviral activity with an EC50 less than or equal to 100 xcexcM in the HI-HeLa cell culture assay.
The present invention preferably relates to compounds of the formula II: 
wherein
R31 is H, F or an alkyl group;
R32 is selected from one of the following moieties: 
wherein
R35 is H, an alkyl group, an aryl group, xe2x80x94OR38, or xe2x80x94NR38R39, and
R36 is H or an alkyl group,
or R35 and R36, together with the atom(s) to which they are attached, form a heterocycloalkyl group or a heteroaryl group;
R41 is H, an alkyl group, an aryl group, xe2x80x94OR38, xe2x80x94SR39, xe2x80x94NR38R39, xe2x80x94NR40NR38R39, or xe2x80x94NR38OR39, or R41 and R36, together with the atom(s) to which they are attached, form a heterocycloalkyl group;
R37 is an alkyl group, an aryl group, or xe2x80x94NR38R39;
wherein R38, R39, and R40 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, or, wherein any two of R38, R39, and R40, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
n is 0, 1 or 2;
R33 is H or an alkyl group;
R34 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an O-alkyl, an O-cycloalkyl group, an O-heterocycloalkyl group, an O-aryl group, an O-heteroaryl group, an S-alkyl group, an NH-alkyl group, an NH-aryl group, an N,N-dialkyl group, or an N,N-diaryl group; and
Z and Z1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, xe2x80x94C(O)R21, xe2x80x94CO2R21, xe2x80x94CN, xe2x80x94C(O)NR21R22, xe2x80x94C(O)NR21OR22, xe2x80x94C(S)R21, xe2x80x94C(S)NR21R22, xe2x80x94NO2, xe2x80x94SOR21, xe2x80x94SO2R21, xe2x80x94SO2NR21R22, xe2x80x94SO(NR21)(OR22), xe2x80x94SONR21, xe2x80x94SO3R21, xe2x80x94PO(OR21)2, xe2x80x94PO(R21)(R22), xe2x80x94PO(NR21R22)(OR23), xe2x80x94PO(NR21R22)(NR23R24), xe2x80x94C(O)NR21NR22R23, or xe2x80x94C(S)NR21NR22R23,
wherein R21, R22, R23, and R24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group,
or Z and Z1, both as defined above, together with the atoms to which they are bonded, form a heterocyclo alkyl group;
and pharmaceutically acceptable prodrugs, salts, and solvates thereof.
As used in the present application, the following definitions apply:
An xe2x80x9calkyl groupxe2x80x9d is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
A xe2x80x9ccycloalkyl groupxe2x80x9d is intended to means a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to the following moieties: 
An xe2x80x9caryl groupxe2x80x9d is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, the following moieties: 
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, the following moieties: 
An xe2x80x9cacyl groupxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94R radical, wherein R is any suitable substituent as defined below.
A xe2x80x9cthioacyl groupxe2x80x9d is intended to mean a xe2x80x94C(S)xe2x80x94R radical, wherein R is any suitable substituent as defined below.
A xe2x80x9csulfonyl groupxe2x80x9d is intended to mean a xe2x80x94SO2R radical, wherein R is any suitable substituent as defined below.
The term xe2x80x9csuitable substituentxe2x80x9d is intended to mean any of the substituents recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to, hydroxy groups, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like.
The term xe2x80x9csuitable organic moietyxe2x80x9d is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxy groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
A xe2x80x9chydroxy groupxe2x80x9d is intended to mean the radical xe2x80x94OH.
An xe2x80x9camino groupxe2x80x9d is intended to mean the radical xe2x80x94NH2.
An xe2x80x9calkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NHR where R is an alkyl group as defined above.
A xe2x80x9cdialkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NRaRb where Ra and Rb are each independently an alkyl group as defined above.
An xe2x80x9calkoxy groupxe2x80x9d is intended to mean the radical xe2x80x94OR where R is an alkyl group as defined above, for example, methoxy, ethoxy, propoxy and the like.
An xe2x80x9calkoxycarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)OR where R is an alkyl group as defined above.
An xe2x80x9calkylsulfonyl groupxe2x80x9d is intended to mean the radical xe2x80x94SO2R where R is an alkyl group as defined above.
An xe2x80x9calkylaminocarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NHR where R is an alkyl group as defined above.
A xe2x80x9cdialkylaminocarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NRaRb where Ra and Rb are each independently an alkyl group as defined above.
A xe2x80x9cmercapto groupxe2x80x9d is intended to mean the radical xe2x80x94SH.
An xe2x80x9calkylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SR where R is an alkyl group as defined above.
A xe2x80x9ccarboxy groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)OH.
A xe2x80x9ccarbamoyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NH2.
An xe2x80x9caryloxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORc where Rc is an aryl group as defined above.
A xe2x80x9cheteroaryloxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORd where Rd is a heteroaryl group as defined above.
An xe2x80x9carylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRc where Rc is an aryl group as defined above.
A xe2x80x9cheteroarylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRd where Rd is a heteroaryl group as defined above.
A xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d is intended to mean a compound that may be converted under physiological conditions or by solvolysis to a compound of formula I or formula II.
A xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formulas I and II.
Examples of pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to a mean a salt that retains the biological effectiveness and properties of the free acids and bases of compounds of formulas I and II and that is not biologically or otherwise undesirable.
Example of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention.
The inventive compounds may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term xe2x80x9coptically purexe2x80x9d is intended to mean a compound which comprises at least a sufficient amount of a single enantiomer to yield a compound having the desired pharmacological activity. Preferably, xe2x80x9coptically purexe2x80x9d is intended to mean a compound that comprises at least 90% of a single isomer (80% enantiomeric excess), preferably at least 95% (90% e.e.), more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
Preferably in the above formulas I and II, R1 and R31 are H or F. Preferably in formula I, R4 is an acyl group or a sulfonyl group. Preferably in formulas I and II, D1 and D2 are xe2x80x94OR25, xe2x95x90O, xe2x95x90S, xe2x89xa1N, xe2x95x90NR25, or xe2x80x94NR25R26, wherein R25 and R26 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the nitrogen atom to which they are bonded, form a heterocycloalkyl group, and more preferably D1 and D2 are xe2x95x90O. Preferably A1 and A2 are C, CH, S, or S(O), and more preferably A1 and A2 are C.
Preferably B1 and B2 are NR17R18, wherein R17 and R18 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or wherein R17 and R18, together with the atom(s) to which they are bonded, form a heterocycloalkyl group.
Preferably Z and Z1 are independently H, an aryl group, or a heteroaryl group, xe2x80x94C(O)R21, xe2x80x94CO2R21, xe2x80x94CN, xe2x80x94C(O)NR21R22, xe2x80x94C(O)NR21OR22, xe2x80x94C(S)R21, xe2x80x94C(S)NR21R22, xe2x80x94NO2, xe2x80x94SOR21, xe2x80x94SO2R21, xe2x80x94SO2NR21R22, xe2x80x94SO(NR21)(OR22), xe2x80x94SONR21, xe2x80x94SO3R21, xe2x80x94C(O)NR21NR22R23, or xe2x80x94C(S)NR21NR22R23; wherein R21, R22, and R23 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, or wherein any two of R21, R22, and R23, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, or Z and Z1, together with the atoms to which they are attached, form a heterocycloalkyl group.
Preferably R32 is one of the following moieties: 
wherein R35, R36, R37, R41 and n are as defined above.
Compounds according to formula I include the following, where * indicates point of attachment:
Compounds 2, 3, 4, 5, 7, 11, 12, 13, 14, 16, 17, 18, 19, 21, 22, 24, 25, 41-43, 74, and 75 having the formula III: 
2. R2 is CH2CH2C(O)NHCPh3, R1 is H, Z is H, and Z1 is CO2CH2CH3 
3. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
4. R2 is CH2NHC(O)CH3; R1 is H, Z is H, and Z1 is CO2CH2CH3 
5. R2 is 
R1 is H, Z is H, and Z1 is CO2CH2CH3 
7. R2 is CH2CH2C(O)NH2, R1 is H, Z is CO2CH3, and Z1 is H
11. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH3 
12. R2 is CH2CH2S(O)CH3, R1 is H, Z is H, and Z1 is CO2CH2CH3 
13. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is C(O)CH3 
14. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CN
16. R2 is CH2NHC(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
17. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH(CH3)2 
18. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is 
19. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is 
21. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is 
22. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is C(O)N(CH3)2 
24. R2 is CH2CH2C(O)NH2; R1 is H, Z is H, and Z1 is C(O)Ph
25. R2 is CH2CH2C(O)NH2; R1 is H, Z is H, and Z1 is 
41. R1 is H; R2 is CH2CH2C(O)NH2; Z is H; and Z1 is 
42. R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is 
43. R1 is H; R2 is CH2CH2C(O)NH2; Z is H; and Z1 is 
74. R1 is H; R2 is CH2CH2C(O)NH2; Z is H; and Z1 is CH2Cl
75. R1 is H; R2 is CH2CH2C(O)NH2; Z is H; and Z1 is 
Compounds (26, 27, and 28) having the formula IV: 
where X1 and X2 independently are H, F, or Cl,
26. R2 is CH2CH2C(O)NH2, X1 is Cl and X2 is H
27. R2 is CH2CH2C(O)NH2, X1 is F and X2 is H
28. R2 is CH2CH2C(O)NH2, X1 is H and X2 is F
Compounds (30-34) having the formula V: 
30. R4 is PhCH2OC(O), X1 is H, R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
31. R4 is CH3CH2CH2SO2, X1 is H, R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
32. R4 is PhCH2SO2, X1 is H, R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
33. R4 is CH3CH2SO2, X1 is H, R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
34. R4 is PhSO2, X1 is H, R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is CO2CH2CH3 
Compound 29 having the formula VI: 
Compound 44 having the formula VII: 
Compounds (35-37) having the formula VIII: 
35. X1 is F, R2 is CH2CH2C(O)NH2, Y is CH, Z is H, and Z1 is CO2CH2CH3 
36. X1 is H, R2 is CH2CH2C(O)NH2, Y is N, Z is H, and Z1 is CO2CH2CH3 
37. X1 is H, R2 is CH2CH2C(O)NH2, Y is CH, Z is H, and Z1 is C(O)N(CH3)OCH3 
Compounds 46-66 and 78 having the formula IX: 
46. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
47. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6 and X1 are H; Y is CH; Z is H; and Z1 is 
48. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
49. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
50. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
51. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
52. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is C(O)tBu
53. R1 is H; R2 is CH2CH2C(O)NH2; R5 and R6 are H; X1 is OH; Y is CH; Z is H; and Z1 is CO2CH2CH3 
54. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is C(O)C(O)CH3 
55. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is C(O)C(O)N(CH3)2 
56. R1 is H; R2 is CH2OC(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is CO2CH2CH3 
57. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z and Z1 together form 
where the S is preferably trans to the R1 group
58. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; and Z and Z1 together form 
59. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is C(O)NHPh
60. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is C(O)N(CH3)Ph
61. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
62. R1 is H; R2 is CH2CH2C(O)NH2; R5, R6, and X1 are H; Y is CH; Z is H; and Z1 is 
63. R1, R5, R6, X1, and Z are H; Y is CH; R2 is CH2CH2C(O)NH2; and Z1 is 
64. R1, R5, R6, X1, and Z are H; Y is CH; R2 is CH2CH2C(O)NH2; and Z1 is 
65. R1, R5, R6, X1, and Z are H; Y is CH; R2 is CH2CH2C(O)NH2; and Z1 is 
66. R1, R5, R6, X1, and Z are H; Y is CH; R2 is CH2CH2C(O)NH2; and Z1 is 
78. R1, R5, R6 and X1 are H; Y is CH; R2 is CH2CH2C(O)NH2; Z is CH2Cl; and Z1 is H
Compounds 67-69 having the formula X: 
67. R1, R5, R6, X1, and Z are H; R2 is CH2CH2C(O)NH2; Z1 is CO2CH2CH3; and Ar is Ph
68. R1, R5, R6, X1, and Z are H; R2 is CH2CH2C(O)NH2; Z1 is CO2CH3; and Ar is 
69. R1, R5, R6, X1, and Z are H; R2 is CH2CH2C(O)NH2; Z1 is CO2CH2CH3; and Ar is 
Compounds 70-73 having the formula XI: 
70. R1, R5, R6, and Z are H; R2 is CH2CH2C(O)NH2; R3 is CH2Ph; Z1 is CO2CH2CH3; and A is 
71. R1, R5, R6, and Z are H; R2 is CH2CH2C(O)NH2; R3 is CH2Ph; Z1 is CO2CH2CH3; and A is Ph
72. R1, R5, R6, and Z are H; R2 is CH2CH2C(O)NH2; A is CH2CH(CH3)2; Z1 is CO2CH2CH3; and R3 is 
73. R1, R5, R6, and Z are H; R2 is CH2CH2C(O)NH2; A is CH2CH(CH3)2; Z1 is CO2CH2CH3; and R3 is 
Compounds 1, 6, 8-10, 15, 20, 23, 38-40, 76, and 77 having the formula XII: 
1. R1 is H; R2 is CH2CH2CN; R5 is H; R6 is H; Z is F; and Z1 is CO2CH2CH3 
6. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is C(O)NHCH2CH3 
8. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is F; and Z1 is CO2CH2CH3 
9. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is SO2CH3 
10. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is SO2Ph
15. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is CO2H
20. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is PO(OCH2CH3)2 
23. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is 
38. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is 
39. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is 
40. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is 
76. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is CH2OAc
77. R1 is H; R2 is CH2CH2C(O)NH2; R5 is H; R6 is H; Z is H; and Z1 is 
Compound 45 having the formula XIII:
45. 
Compounds 79-97, also having the formula III: 
82. R2 is CH2CH2C(O)NH2, R1 is H, Z is CH3 and Z1 is CO2CH2CH3 
90. R2 is CH2CH2C(O)NH2, R1 is H, and Z and Z1 together form 
where Cxe2x95x90O is preferably cis to the R1 group
or wherein R2 is CH2CH2C(O)NH2, R1 is H, Z is H, and Z1 is selected from: 
Compounds 98-121 having formula XIV: 
wherein R6 is H, R1 is H, R2 is CH2CH2C(O)NH2, Z is H, Z1 is CO2CH2CH3 and
98. R3 is CH2Ph and R4 is 
99. R3 is H and R4 is 
100. R3 is 
and R4 is 
101. R3 is CH2Ph and R4 is 
102. R3 is CH2Ph and R4 is 
103. R3 is 
and R4 is 
104. R3 is CH2Ph and R4 is 
105. R3 is 
and R4 is 
106. R3 is CH2Ph and R4 is 
107. R3 is CH2Ph and R4 is 
108. R3 is CH2CH3 and R4 is 
109. R3 is CH3 and R4 is 
110. R3 is CH2Ph and R4 is 
111. R3 is CH2Ph and R4 is 
112. R3 is 
and R4 is 
113. R3 is 
and R4 is 
114. R3 is 
and R4 is 
115. R3 is CH2Ph and R4 is 
116. R3 is CH2Ph and R4 is 
117. R3 is CH2Ph and R4 is 
118. R3 is CH2Ph and R4 is 
119. R3 is CH2Ph and R4 is 
120. R3 is CH2Ph and R4 is 
121. R3 CH2CH2CO2H and R4 is 
Compounds 122-130, also having the formula XIV: 
wherein R6 is H, R1 is H, R3 is CH2Ph and
122. R2 is CH2OC(O)NHC(O)CH2Cl, Z is H, Z1 is CO2CH2CH3 and R4 is 
123. R2 is CH2CH2C(O)NH2, Z is H, Z1 is CO2CH2CH3 and R4 is 
124. R2 is CH2CH2C(O)NH2, Z is H, Z1 is 
and R4 is 
125. R2 is CH2CH2C(O)NH2, Z is H, Z1 is NO2, and R4 is 
126. R2 is CH2CH2C(O)NH2, Z is H, Z1 is 
and R4 is 
127. R2 is CH2CH2C(O)NH2, Z is H, Z1 is 
and R4 is 
128. R2 is CH2CH2C(O)NH2, Z is H, Z1 is 
and R4 is 
129. R2 is CH2CH2C(O)NH2, Z is H, Z1 is CO2CH2CH3 and R4 is 
130. R2 is CH2CH2C(O)NH2, Z and Z1 together form 
and R4 is 
where Cxe2x95x90O is preferably cis to the R1 group.
Compounds 131-145, also having the formula XIV: 
wherein R6 is H, R1 is H, R2 is CH2CH2C(O)NH2, R4 is 
131. R3 is CH2Ph, Z is H and Z1 is 
132. R3 is 
Z is H and Z1 is CO2CH2CH3 
133. R3 is 
Z is H and Z1 is CO2CH2CH3 
134. R3 is CH(OH)CH3, Z is H and Z1 is CO2CH2CH3 
135. R3 is 
Z is H and Z1 is CO2CH2CH3 
136. R3 is 
Z is H and Z1 is CO2CH2CH3 
137. R3 is CH2CH2CH3, Z is H and Z1 is CO2CH2CH3 
138. R3 is CH2Ph, Z is H and Z1 is C(O)N(OH)CH3 
139. R3 is 
Z is H and Z1 is CO2CH2CH3 
140. R3 is 
Z is H and Z1 is CO2CH2CH3 
141. R3 is CH2CH(CH3)2, Z is H and Z1 is CO2CH2CH3 
142. R3 is CH2SCH3, Z is H and Z1 is CO2CH2CH3 
143. R3 is CH2SCH2CH3, Z is H, and Z1 is CO2CH2CH3 
144. R3 is CH2Ph, Z is CH3, and Z1 is CO2H,
145. R3 is CH2Ph, Z is H, and Z1 is 
Compounds 146-155, also having the formula XIV: 
wherein R6 is H, R1 is H, R2 is CH2CH2C(O)NH2, Z is H, and
146. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
147. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
148. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
149. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
150. Z1 is 
R3 is CH2Ph, and R4 is 
151. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
152. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
153. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
154. Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
155. Z1 is CO2CH2CH3, R3 is 
and R4 is 
Compounds 156-173, also having formula XIV: 
wherein R6 is H, R3 is CH2Ph, R2 is CH2CH2C(O)NH2, and
156. R1 is OH, Z is H, Z1 is CO2CH2CH3, and R4 is 
157. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
158. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
159. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
160. R1 is H, Z is H, Z1 is 
and R4 is 
161. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
162. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
163. R1 is H, Z is H, Z1 is CO2CH2C(CH3)3, and R4 is 
164. R1 is H, Z and Z1 together form 
and R4 is 
where Cxe2x95x90O is preferably cis to the R1 group
165. R1 H, Z is H, Z1 is CO2CH2CH3, and R4 is 
166. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
167. R1 is H, Z is H, Z1 is CO2CH2CH3and R4 is 
168. R1 is H, Z is CH3, Z1 is CO2CH2CH3, and R4 is 
169. R1 is H, Z and Z1 together form 
and R4 is 
where Cxe2x95x90O is preferably cis to R1 
170. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
171. R1 is H, Z is CH3, Z1 is CO2CH2CH3, and R4 is 
172. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
173. R1 is H, Z is H, Z1 is CO2CH2CH3, and R4 is 
Compounds 174-188, also having the formula XIV: 
wherein R6 is H, R2 is CH2CH2C(O)NH2, R1 is H, and
174. Z is H, Z1 is CO2CH2CH3, R3 is 
and R4 is 
175. Z is CH3, Z1 is CO2CH2CH3, R3 is 
and R4 is 
176. Z is H, Z1 is CO2CH2CH3, R3 is 
and R4 is 
177. Z is CH3, Z1 is CO2CH2CH3, R3 is 
and R4 is 
178. Z is H, Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
179. Z is H, Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
180. Z is H, Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
181. Z and Z1 together form 
R3 is 
and R4 is 
where Cxe2x95x90O is preferably cis to the R1 group
182. Z is H, Z1 is CO2CH2CH3, R3 is CH2Ph, and R4 is 
183. Z is H, Z1 is CO2CH2CH3, R3 is 
and R4 is 
184. Z is H, Z1 is CO2CH2CH3, R3 is 
and R4 is 
185. Z is H, Z1 is CO2CH2CH3, R3 is 
and R4 is 
186. Z is H, Z1 is CO2CH2Ph, R3 is 
and R4 is 
187. Z is CH3, Z1 is CO2CH2CH3, R3 is CH2Ph and R4 
is
188. Z is H, Z1 is CO2CH2CH2OCH3, R3 is 
and R4 is 
189. R3 is 
R4 is 
and Z and Z1 together form 
where Cxe2x95x90O is preferably cis to the R1 group
190. Z is H, Z1 is CO2CH2CH3, R3 is 
and R4 is 
Other compounds according to the invention include the following compounds of formula III: 
wherein R6 is H, R1 is H, R3 is CH2Ph, R2 is CH2CH2C(O)NH2, Z is H, Z1 is CO2CH2CH3, and R4 is selected from the following: 
wherein VAR is selected from xe2x80x94CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2xe2x80x94Ph, 
The present invention is further directed to methods of inhibiting picornaviral 3C protease activity that comprises contacting the protease for the purpose of such inhibition with an effective amount of a compound of formula I or a pharmaceutically acceptable prodrug, salt, or solvate thereof. For example, one can inhibit picornaviral 3C protease activity in mammalian tissue by administering a compound of formula I or II or a pharmaceutically acceptable prodrug, salt, or solvate thereof. More particularly, the present invention is directed to methods of inhibiting rhinoviral protease activity.
The activity of the inventive compounds as inhibitors of picornaviral 3C protease activity may be measured by any of the methods available to those skilled in the art, including in vivo and in vitro assays. Examples of suitable assays for activity measurements include the Antiviral HIxe2x80x94HeLa Cell Culture Assay and Normal Human Bronchial Epithelial Cell Assay, both described herein.
Administration of the compounds of the formulas I and II, or their pharmaceutically acceptable prodrugs, salts, and solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include, but are not limited to, oral, nasal, parenteral, topical, transdermal and rectal.
The inventive compounds of formulas I and II, and their pharmaceutically acceptable prodrugs, salts, and solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid, or lyopholized formulations, such as tablets, powders, capsules, suppositories, suspensions and aerosols. The pharmaceutical composition may also include suitable excipients, diluents, vehicles and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating and compressing when necessary for tablet forms, or mixing, filling and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraural and/or rectal administration.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers may include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of formula I or II or a pharmaceutically acceptable prodrug, salt, or solvate thereof) and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of 3C protease activity, by any known method of administering the dose including topical, for example, as an ointment or cream; orally, rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or intraocular infusion.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean that amount of a compound of formula I or II that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picarnoviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus. The amount of a given compound of formula I or II that will correspond to a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, but can nevertheless be readily determined by one of skill in the art.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more picarnoviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephaiomyocarditis viruses, menigovirus, and hepatitis A virus, and includes:
(a) prophylactic treatment in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but not yet diagnosed as having it;
(b) inhibiting the disease condition; and/or
(c) alleviating, in whole or in part, the disease condition.
The inventive compounds, and their salts, solvates, and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described below.
Preferably, the inventive compounds of formulas I and II are prepared by the novel methods of the present invention, including the four general methods shown below. In each of these general methods, R1, R2, R3, R4, R5, R6, Z, and Z1 are as defined above.
General Method I: 
In General Method I, protected amino acid A, where P1 is an appropriate protecting group for nitrogen, is subjected to an amide forming reaction with amino alcohol (or salt thereof) B to produce amide C. Amide C is then deprotected to give free amine (or salt thereof) D. Amine D and Compound E, where xe2x80x9cLvxe2x80x9d is an appropriate leaving group, are subjected to a bond forming reaction generating compound F. Compound F is oxidized to intermediate G, which is then transformed into unsaturated product H. If protecting groups are used on any R groups (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
An alternative method to prepare intermediate F is described as follows: 
Compound E and amino acid (or salt thereof) I, where P2 is an appropriate protecting group for oxygen, are subjected to a bond forming reaction to produce intermediate J. Intermediate J is deprotected to yield free carboxylic acid K, which is subsequently subjected to an amide forming reaction with amino alcohol (or salt thereof) B to generate intermediate F.
Amino alcohol B can be prepared as follows: 
Amino acid L, where P1 is an appropriate protecting group for nitrogen, is converted to carbonyl derivative M, where xe2x80x9cLvxe2x80x9d is a leaving group. Compound M is subjected to a reaction where xe2x80x9cLvxe2x80x9d is reduced to protected amino alcohol Q. Amino alcohol Q is deprotected to give amino alcohol B.
General Method II: 
In General Method II, amino acid L, where P1 is an appropriate protecting group for nitrogen, is converted to a carbonyl derivative M, where xe2x80x9cLvxe2x80x9d is a leaving group. Compound M is subjected to a reaction where xe2x80x9cLvxe2x80x9d is replaced by R1 to give derivative N. Derivative N is then transformed into unsaturated product O. Unsaturated compound O is deprotected to give free amine (or salt thereof) P, or modified one or more times at R2, R5, Z and/or Z1 to give one or more modified O compounds.
Modified O is then deprotected to give amine (or salt thereof) P. Amine P is subsequently subjected to an amide forming reaction with carboxylic acid K, prepared as described in General Method I, to give final product H. If protecting groups were used on any R group (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
An alternative method to prepare intermediate N is described as follows: 
Compound M is subjected to a reaction where xe2x80x9cLvxe2x80x9d is reduced to protected amino alcohol Q. Amino alcohol Q is subsequently oxidized to derivative N.
General Method III: 
In General Method III, amino acid L, where P1 is an appropriate protecting group for nitrogen, is converted to a carbonyl derivative M, where xe2x80x9cLvxe2x80x9d is a leaving group. Derivative M is deprotected to give free amine (or salt thereof) R, which subsequently is subjected to an amide forming reaction with carboxylic acid K to give intermediate S. Intermediate S is then either converted directly to carbonyl intermediate G, or successively reduced to alcohol F, which is then oxidized to G. Intermediate G is subjected to a reaction to yield the unsaturated final product H. If protecting groups were used on any R groups (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
General Method IV: 
In General Method IV, free amine (or salt thereof) P, prepared from intermediate O as described in General Method II, is converted to amide T by reaction with amino acid A, where P1 is an appropriate protecting group for nitrogen. Compound T is further deprotected to free amine (or salt thereof) U, which is subsequently converted to H with reactive intermediate E. If protecting groups were used on any R groups (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
Preferably the compound of formulas I or II can be prepared by one of four specific methods. For example, compounds 4, 12, 14, 16, 20, 23, 24, 26-30, 35, and 36 can be prepared by Specific Method I: 
In Specific Method I, carboxylic acid K, CBZ-L-Leu-L-Phe, which can be purchased from Bachem or prepared as described in General Method I, is subjected to an amide forming reaction with amino alcohol (or salt thereof) B to generate intermediate F. Intermediate F is oxidized to intermediate G, which is then transformed into unsaturated product H. In the case of Compound 12, intermediate F is oxidized to modified F, which is then oxidized to intermediate G. If protecting groups were used on any R groups (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
For example, compounds 1-3, 6-11, 17-19, 21, 22, 25, 37-40, and 74-77 can be prepared by Specific Method II: 
In Specific Method II, intermediate P (or salt thereof), prepared as described in General Method II, is subjected to an amide forming reaction with carboxylic acid K, CBZ-L-Leu-L-Phe, which can be purchased from Bachem or prepared as described in General Method I, to give final product H. If protecting groups were used on any R group (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
For example, compounds 5, 13, and 15 can be prepared by Specific Method III. 
In Specific Method III, free amine (or salt thereof) R, prepared as described in General Method III, is subjected to an amide forming reaction with carboxylic acid K, CBZ-L-Leu-L-Phe, which can be purchased from Bachem or prepared as described in General Method I, to give intermediate S. Intermediate S is then either converted directly to carbonyl intermediate G, in the case of compounds 13 and 15, or reduced to alcohol F, which is then oxidized to intermediate G, in the case of compound 5. Intermediate G is subjected to a reaction to yield the unsaturated final product H. If protecting groups were used on any R groups (R1-R6) and/or on Z, and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
For example, compounds 31-34 can be prepared by Specific Method IV: 
In Specific Method IV, free amine (or salt thereof) P, prepared as described in General Method II, is converted to amide T by reaction with protected amino acid A, which can be purchased from Bachem, Advanced Chemtech, and Synthetech. Compound T is further deprotected to free amine (or salt thereof) U, which is subsequently converted to H with reactive intermediate E. If protecting groups were used on any R groups (R1-R6) and/or on Z and/or Z1, product H is deprotected and/or further modified to yield xe2x80x9cdeprotected or modified H.xe2x80x9d
Suitable protecting groups for nitrogen are recognizable to those skilled in the art and include, but are not limited to benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, p-methoxybenxyloxycarbonyl, trifluoroacetamie, and p-toluenesulfonyl. Suitable protecting groups for oxygen are recognizable to those skilled in the art and include, but are not limited to xe2x80x94CH3, xe2x80x94CH2CH3, tBu, xe2x80x94CH2Ph, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2OCH2CH2Si(CH3)3, and xe2x80x94CH2CCl3. Other examples of suitable protecting groups for nitrogen or oxygen can be found in T. Green and P. Wuts, Protecting Groups in Organic Synthesis (2nd ed. 1991), which is incorporated herein by reference.
Suitable leaving groups are recognizable to those skilled in the art and include, but are not limited to, Cl, Br, I, sulfonates, O-alkyl groups, 
Other examples of suitable leaving groups are described in J. March, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure (4th ed. 1992) at pages 205, 351-56, 642-43, 647, 652-53, 666, 501, 520-21, 569, 579-80, 992-94, 999-1000, 1005, and 1008, which are incorporated herein by reference.